Peptides Derived from Vascular Endothelial Growth Factor B Show Potent Binding to Neuropilin-1

Vascular endothelial growth factors (VEGFs) regulate significant pathways in angiogenesis, myocardial and neuronal protection, metabolism, and cancer progression. The VEGF-B isoform is involved in cell survival, anti-apoptotic and antioxidant mechanisms, through binding to VEGF receptor 1 and neuropilin-1 (NRP-1). We employed surface plasmon resonance technology and X-ray crystallography to analyse the molecular basis of the interaction between VEGF-B and the b1 domain of NRP-1, and developed VEGF-B - C-terminus derived peptides to be used as chemical tools for studying VEGF-B - NRP-1 related pathways. Peptide lipidation was used as a means to stabilise the peptides. VEGF-B - derived peptides containing a C-terminal arginine show potent binding to NRP1-b1. Peptide lipidation increased binding residence time and improved plasma stability. A crystal structure of a peptide with NRP-1 demonstrated that VEGF-B peptides bind at the canonical C-terminal Arginine binding site. VEGF-B C-terminus imparts higher affinity for NRP-1 than the corresponding VEGF-A_{165} region. This tight binding may impact on the activity and selectivity of the full-length protein. The VEGF-B_{167} derived peptides were more effective than VEGF-A_{165} peptides in blocking functional phosphorylation events. Blockers of VEGF-B function have potential applications in diabetes and non-alcoholic fatty liver disease

Improving the use of research evidence in guideline development: 11. Incorporating considerations of cost-effectiveness, affordability and resource implications

BACKGROUND: The World Health Organization (WHO), like many other organisations around the world, has recognised the need to use more rigorous processes to ensure that health care recommendations are informed by the best available research evidence. This is the 11(th )of a series of 16 reviews that have been prepared as background for advice from the WHO Advisory Committee on Health Research to WHO on how to achieve this. OBJECTIVES: We reviewed the literature on incorporating considerations of cost-effectiveness, affordability and resource implications in guidelines and recommendations. METHODS: We searched PubMed and three databases of methodological studies for existing systematic reviews and relevant methodological research. We did not conduct systematic reviews ourselves. Our conclusions are based on the available evidence, consideration of what WHO and other organisations are doing and logical arguments. KEY QUESTIONS AND ANSWERS: When is it important to incorporate cost-effectiveness, resource implications and affordability considerations in WHO guidelines (which topics)? • For cost-effectiveness: The need for cost/effectiveness information should be dictated by the specific question, of which several may be addressed in a single guideline. It is proposed that the indications for undertaking a cost-effectiveness analysis (CEA) could be a starting point for determining which recommendation(s) in the guideline would benefit from such analysis. • For resource implications/affordability: The resource implications of each individual recommendation need to be considered when implementation issues are being discussed. How can cost-effectiveness, resource implications and affordability be explicitly taken into account in WHO guidelines? • For cost-effectiveness: ∘ If data are available, the ideal time to consider cost-effectiveness is during the evidence gathering and synthesizing stage. However, because of the inconsistent availability of CEAs and the procedural difficulty associated with adjusting results from different CEAs to make them comparable, it is also possible for cost-effectiveness to be considered during the stage of developing recommendations. ∘ Depending on the quantity and quality and relevance of the data available, such data can be considered in a qualitative way or in a quantitative way, ranging from a listing of the costs to a modelling exercise. At the very least, a qualitative approach like a commentary outlining the economic issues that need to be considered is necessary. If a quantitative approach is to be used, the full model should be transparent and comprehensive. • For resource implications/affordability: ∘ Resource implications, including health system changes, for each recommendation in a WHO guideline should be explored. At the minimum, a qualitative description that can serve as a gross indicator of the amount of resources needed, relative to current practice, should be provided. How does one provide guidance in contextualizing guideline recommendations at the country level based on considerations of cost-effectiveness, resource implications and affordability? • All models should be made available and ideally are designed to allow for analysts to make changes in key parameters and reapply results in their own country. • In the global guidelines, scenarios and extensive sensitivity/uncertainty analysis can be applied. Resource implications for WHO • From the above, it is clear that guidelines development groups will need a health economist. There is need to ensure that this is included in the budget for guidelines and that there is in-house support for this as well

Cost-effectiveness of HBV and HCV screening strategies:a systematic review of existing modelling techniques

Introduction: Studies evaluating the cost-effectiveness of screening for Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) are generally heterogeneous in terms of risk groups, settings, screening intervention, outcomes and the economic modelling framework. It is therefore difficult to compare cost-effectiveness results between studies. This systematic review aims to summarise and critically assess existing economic models for HBV and HCV in order to identify the main methodological differences in modelling approaches. Methods: A structured search strategy was developed and a systematic review carried out. A critical assessment of the decision-analytic models was carried out according to the guidelines and framework developed for assessment of decision-analytic models in Health Technology Assessment of health care interventions. Results: The overall approach to analysing the cost-effectiveness of screening strategies was found to be broadly consistent for HBV and HCV. However, modelling parameters and related structure differed between models, producing different results. More recent publications performed better against a performance matrix, evaluating model components and methodology. Conclusion: When assessing screening strategies for HBV and HCV infection, the focus should be on more recent studies, which applied the latest treatment regimes, test methods and had better and more complete data on which to base their models. In addition to parameter selection and associated assumptions, careful consideration of dynamic versus static modelling is recommended. Future research may want to focus on these methodological issues. In addition, the ability to evaluate screening strategies for multiple infectious diseases, (HCV and HIV at the same time) might prove important for decision makers

A pilot Internet "Value of Health" Panel: recruitment, participation and compliance

Objectives To pilot using a panel of members of the public to provide preference data via the Internet Methods A stratified random sample of members of the general public was recruited and familiarised with the standard gamble procedure using an Internet based tool. Health states were perdiodically presented in "sets" corresponding to different conditions, during the study. The following were described: Recruitment (proportion of people approached who were trained); Participation (a) the proportion of people trained who provided any preferences and (b) the proportion of panel members who contributed to each "set" of values; and Compliance (the proportion, per participant, of preference tasks which were completed). The influence of covariates on these outcomes was investigated using univariate and multivariate analyses. Results A panel of 112 people was recruited. 23% of those approached (n = 5,320) responded to the invitation, and 24% of respondents (n = 1,215) were willing to participate (net = 5.5%). However, eventual recruitment rates, following training, were low (2.1% of those approached). Recruitment from areas of high socioeconomic deprivation and among ethnic minority communities was low. Eighteen sets of health state descriptions were considered over 14 months. 74% of panel members carried out at least one valuation task. People from areas of higher socioeconomic deprivation and unmarried people were less likely to participate. An average of 41% of panel members expressed preferences on each set of descriptions. Compliance ranged from 3% to 100%. Conclusion It is feasible to establish a panel of members of the general public to express preferences on a wide range of health state descriptions using the Internet, although differential recruitment and attrition are important challenges. Particular attention to recruitment and retention in areas of high socioeconomic deprivation and among ethnic minority communities is necessary. Nevertheless, the panel approach to preference measurement using the Internet offers the potential to provide specific utility data in a responsive manner for use in economic evaluations and to address some of the outstanding methodological uncertainties in this field

Survival and hepatitis status among Asian Americans with hepatocellular carcinoma treated without liver transplantation

<p>Abstract</p> <p>Background</p> <p>Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) are established causes of HCC. HCC patients are often diagnosed late and receive palliative therapies, however, the survival of Asian American patients with HCC treated without transplantation has not been well studied. We reviewed our institution's experience to determine predictors and rates of survival in Asian American HCC patients treated without transplantation.</p> <p>Methods</p> <p>We identified Asian American patients with HCC referred to M. D. Anderson Cancer Center. Patients were tested for HBV and HCV. Survival curves were generated by Kaplan-Meier method. Multivariate Cox proportional hazards regression was used to test the relationship between prognostic factors and survival.</p> <p>Results</p> <p>Of 82 Asian American HCC patients, most had advanced disease (65%) and received treatment (68%); however, only 11% had surgical resection. 94% had positive anti-HBc and 61% had positive HBsAg. 20% had positive anti-HCV. There were no significant changes in the rates of HBV and HCV over time. Male gender, high alpha-fetoprotein levels, and stage IV disease were associated with shorter survival Overall median survival was 9.2 months (95% CI 6.5–11.9), and the survival of HCV and HBV patients was not statistically different.</p> <p>Conclusion</p> <p>The survival rate of Asian American patients with advanced HCC, for whom transplantation was not available, was low. Timely hepatitis screening and interventions by primary care physicians may be the most logical solution to reduce the burden of hepatitis-associated HCC among Asian Americans.</p

Plate-boundary deformation associated with the great Sumatra–Andaman earthquake

The Sumatra–Andaman earthquake of 26 December 2004 is the first giant earthquake (moment magnitude M_w > 9.0) to have occurred since the advent of modern space-based geodesy and broadband seismology. It therefore provides an unprecedented opportunity to investigate the characteristics of one of these enormous and rare events. Here we report estimates of the ground displacement associated with this event, using near-field Global Positioning System (GPS) surveys in northwestern Sumatra combined with in situ and remote observations of the vertical motion of coral reefs. These data show that the earthquake was generated by rupture of the Sunda subduction megathrust over a distance of >1,500 kilometres and a width of <150 kilometres. Megathrust slip exceeded 20 metres offshore northern Sumatra, mostly at depths shallower than 30 kilometres. Comparison of the geodetically and seismically inferred slip distribution indicates that ~30 per cent additional fault slip accrued in the 1.5 months following the 500-second-long seismic rupture. Both seismic and aseismic slip before our re-occupation of GPS sites occurred on the shallow portion of the megathrust, where the large Aceh tsunami originated. Slip tapers off abruptly along strike beneath Simeulue Island at the southeastern edge of the rupture, where the earthquake nucleated and where an M_w = 7.2 earthquake occurred in late 2002. This edge also abuts the northern limit of slip in the 28 March 2005 M_w = 8.7 Nias–Simeulue earthquake

Epidemiology characteristics, methodological assessment and reporting of statistical analysis of network meta-analyses in the field of cancer

Because of the methodological complexity of network meta-analyses (NMAs), NMAs may be more vulnerable to methodological risks than conventional pair-wise meta-analysis. Our study aims to investigate epidemiology characteristics, conduction of literature search, methodological quality and reporting of statistical analysis process in the field of cancer based on PRISMA extension statement and modified AMSTAR checklist. We identified and included 102 NMAs in the field of cancer. 61 NMAs were conducted using a Bayesian framework. Of them, more than half of NMAs did not report assessment of convergence (60.66%). Inconsistency was assessed in 27.87% of NMAs. Assessment of heterogeneity in traditional meta-analyses was more common (42.62%) than in NMAs (6.56%). Most of NMAs did not report assessment of similarity (86.89%) and did not used GRADE tool to assess quality of evidence (95.08%). 43 NMAs were adjusted indirect comparisons, the methods used were described in 53.49% NMAs. Only 4.65% NMAs described the details of handling of multi group trials and 6.98% described the methods of similarity assessment. The median total AMSTAR-score was 8.00 (IQR: 6.00-8.25). Methodological quality and reporting of statistical analysis did not substantially differ by selected general characteristics. Overall, the quality of NMAs in the field of cancer was generally acceptable

Economic evaluation of fulvestrant as an extra step in the treatment sequence for ER-positive advanced breast cancer

Drug therapies for advanced breast cancer in hormone-receptor-positive disease include both hormonal and chemotherapies. Current UK practice is to minimise toxicity by using sequential hormonal agents for as long as clinically appropriate. A Markov model was developed to investigate the cost effectiveness of different sequences of therapies, particularly exploring the effects of adding an additional hormonal agent, fulvestrant, to the treatment pathway. A systematic review was undertaken and a panel of seven UK oncologists validated assumptions used for treatment efficacy, treatment pathways and resources used. Fulvestrant was found to be a cost-effective treatment option when added to the treatment sequence as a second- or third-line hormonal therapy for advanced disease. For a cohort of 1000 patients, fulvestrant as a second-line hormone therapy provided an additional 47 life years and 41 quality-adjusted life years (QALYs), at an additional cost of £301 359. This equated to £6500 per life years gained and £7500 per QALY. When used as a third-line option, the fulvestrant arm was dominant providing an increase in health benefit of 27 QALYs for the whole cohort, at a mean overall cost reduction of £430 per patient. Sensitivity analyses showed these results to be robust, demonstrating that fulvestrant is an economically viable additional endocrine option in the United Kingdom for the treatment of hormone responsive advanced breast cancer

Cardiovascular and renal outcomes of renin-angiotensin system blockade in adult patients with diabetes mellitus: a systematic review with network meta-analyses

Medications aimed at inhibiting the renin-angiotensin system (RAS) have been used extensively for preventing cardiovascular and renal complications in patients with diabetes, but data that compare their clinical effectiveness are limited. We aimed to compare the effects of classes of RAS blockers on cardiovascular and renal outcomes in adults with diabetes